He was the adjutant of the Corps of Engineers during the Mexican-American War, seeing action at the siege of Vera Cruz and at Cerro Gordo, Contreras, and Churubusco. In the latter fight, he caught the attention of his superiors, who rewarded him with the brevet rank of captain. He was again cited and breveted for gallantry at the Battle of Chapultepec, this time to the rank of Major. He saw further combat at Molino del Rey, and the Battle for Mexico City, where he was severely wounded. He later wrote a book on his adventures, Campaigns of the Rio Grande and Mexico, with Notices of the Recent Work of Major Ripley (New York, 1851).

He superintended fortifications on the New England coast from 1841 until 1849, when he assumed command of the coast survey office in Washington, D. C., serving in that role until March 1853.

Having been a firm supporter of Franklin Pierce's candidacy for President of the United States in 1852, Stevens was rewarded by President Pierce on March 17, 1853[2] by being named governor of the newly created Washington Territory (a position which carried with it the title of Superintendent of Indian Affairs for that region). Stevens chose to add one more duty as he traveled west to the territory he would govern: the government was calling for a surveyor to map an appropriate railroadroute across the northern United States, and with Stevens' engineering experience (and likely the favor of Pierce yet again) he won the bid, and spent most of 1853 moving slowly across the prairie, surveying his way to Washington Territory, where he took up his post at Olympia as governor in November that year.

As a result of his expedition, Stevens wrote a third book, Report of Explorations for a Route for the Pacific Railroad near the 47th and 49th Parallels of North Latitude, from St. Paul, Minnesota, to Puget Sound, (commissioned and published by the United States Congress) (2 vols., Washington, 1855–60).

Stevens was a controversial governor in his time, and has become more controversial in retrospect. He used a careful combination of intimidation and force to compel the Native American tribes of Washington Territory to sign treaties that handed over most of their lands and rights to Stevens' government. These included the Treaty of Medicine Creek, Treaty of Hellgate, Treaty of Neah Bay, Treaty of Point Elliott, Point No Point Treaty, and Quinault Treaty. When Stevens was met with resistance, he used the troops at his disposal to exact vengeance. His winter campaign against the Yakama tribe, led by Chief Kamiakin, and his execution of the Nisqually chieftain Leschi (for the crime of having killed Stevens' soldiers in open combat), among other deeds, led a number of powerful citizens in the territory to beg Pierce to remove Stevens. Territorial Judge Edward Lander and Ezra Meeker (an influential private citizen) were both vocal in opposing Stevens—Lander was arrested as a result, and Meeker was simply ignored. Pierce sent word to Stevens of his disapproval of Stevens' conduct, but refused to remove the governor. Those who opposed Stevens ultimately lost public support, as the majority of the citizens of Washington Territory saw Meeker as being on the side of the "Indians", and Stevens on the side of the white settlers.

As a result of this public perception, Stevens was popular enough to be elected the territory's delegate to the United States Congress in 1857 and 1858. The tensions between the whites and the Native Americans would be left for others to resolve—Stevens is often charged with responsibility for the later conflicts in eastern Washington and Idaho, especially the war fought by the United States against Chief Joseph and the Nez Perce, but these events were decades away when Isaac Stevens left Washington for good in 1857.

Hazard Stevens, Isaac's son, was also injured in the Battle of Chantilly. He also became a general in the U.S. Army and an author, and along with P. B. Van Trump participated in the first documented ascent of Mount Rainier.[5]

Two U.S. Army forts were named for Stevens—Fort Stevens in the Union defenses of Washington DC and Fort Stevens in Oregon, which was active from 1863 until 1947 to protect the mouth of the Columbia River.